1. Field of the Invention
The present invention relates to a sequential high throughput screening (HTS) method and system.
2. Discussion of Related Art
In experimental reaction systems, each potential combination of reactant, catalyst and condition should be evaluated in a manner that provides correlation to performance in a production scale reactor. Combinatorial organic synthesis (COS) is an HTS methodology that was developed for pharmaceuticals. COS uses systematic and repetitive synthesis to produce diverse molecular entities formed from sets of chemical “building blocks.” As with traditional research, COS relies on experimental synthesis methodology. However instead of synthesizing a single compound, COS exploits automation and miniaturization to produce large libraries of compounds through successive stages, each of which produces a chemical modification of an existing molecule of a preceding stage. The procedure provides large libraries of diverse compounds that can be screened for various activities.
The techniques used to prepare such libraries involve a stepwise or sequential coupling of building blocks to form the compounds of interest. For example, Pirrung et al., U.S. Pat. No. 5,143,854 ostensibly discloses a technique for generating arrays of peptides and other molecules using, for example, light-directed, spatially-addressable synthesis techniques. Pirrung synthesized polypeptide arrays on a substrate by attaching photoremovable groups to the surface of the substrate, exposing selected regions of the substrate to light to activate those regions, attaching an amino acid monomer with a photoremovable group to the activated region, and repeating the steps of activation and attachment until polypeptides of the desired length and sequences are synthesized.
According to the teachings of Pirrung, each synthesis requires bringing the array to reaction conditions, which requires time. If multiple synthesis steps are utilized as is often the case, each synthesis step should be carefully controlled to achieve uniform reaction conditions and time. Uniform reaction conditions and time periods are difficult to achieve with batch processing of array plates. Further, it is difficult to define and control reaction time with batch processing, since each array plate must be individually “ramped” to target synthesis conditions and then “backed off” from the conditions upon completing the reaction. Considerable manual manipulation may be required at startup and shutdown in adjusting controls, loading samples and bolting enclosures.
Additionally, a high pressure reactor large enough to hold an array plate would require thick walls that cause a delay in controlling temperature. Adjustment of temperature within the reactor always lags behind adjustment at the temperature control. This can be a serious problem where precise temperature control is required. For example, catalyst reaction studies typically require temperature measurement and control to better than ±2° C. (preferably ±0.5° C.).
There is a need for an HTS method and system to easily conduct multiple syntheses under identical or precisely controlled variable conditions and reaction times.